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01.
arXiv (CS.CV) 2026-06-17

Effective Gaussian Management for High-fidelity Object Reconstruction

This paper proposes an effective Gaussian management framework for high-fidelity scene reconstruction of both appearance and geometry. Unlike recent Gaussian Splatting (GS) pipelines that treat all primitives uniformly during optimization, our framework explicitly manages the attribute activation, representation and pruning of Gaussian. Specifically, our framework first introduces GauSep, a novel densification strategy that selectively activates Gaussian color or normal attributes to alleviate destructive gradient conflicts arising from dual supervision. We further propose GauRep, an adaptive Gaussian representation that dynamically adjusts spherical harmonics (SHs) orders and performs task-decoupled pruning to reduce redundancy at both the individual and global levels. To provide reliable geometric supervision for above mangement process, we additionally introduce CoRe, an regularized surface reconstruction module that distills robust normal fields from an SDF branch to the Gaussian representation through a confidence mechanism. Notably, the proposed Gaussian management is compatible with various reconstruction architectures and can be seamlessly integrated to improve performance while reducing size of the model. Extensive experiments demonstrate that our approach achieves superior or comparable performance in appearance and geometry reconstruction compared with state-of-the-art methods, while using significantly fewer parameters.

02.
arXiv (CS.CL) 2026-06-19

Actionable Activation Directions for Detecting and Mitigating Emergent Misalignment Across Language Model Families

Fine-tuning language models on insecure code induces emergent misalignment with poorly understood internal structure. We investigate whether this misalignment corresponds to a causally actionable activation-space direction shared across architectures. Across four instruction-tuned model families (Qwen2.5-1.5B, Gemma-2-2B, Llama-3.2-1B, Ministral-3-3B) finetuned identically, a difference-in-means direction achieves 99.6% separation of aligned and misaligned activations at each model's final layer. Causal steering by subtracting this direction reduces code spillover by 21-51 points, while a secure-code control confirms content specificity. Cross-architecture transfer via ridge regression maps yields large behavioral suppression (up to 46 points) but fails specificity controls as random and orthogonal directions perform comparably. We identify a two-tier specificity structure: within-model directions are causally specific and actionable; cross-model directions are causally real but non-specific. An asymmetric transfer topology emerges, with Gemma and Qwen acting as geometric donors and Llama as a receiver. These findings define the limits of linear cross-architecture correction and recommend within-model probing for auditing.

03.
arXiv (quant-ph) 2026-06-17

When Renormalisation Remembers: UV/IR Mixing as an Entanglement Bridge

作者:

arXiv:2606.17147v1 Announce Type: cross Abstract: Renormalisation is traditionally understood to be a Wilsonian memoryless process in which ultraviolet (UV) degrees of freedom gradually decouple, leaving an autonomous infrared (IR) description. However this need not be the case: in UV/IR mixed theories correlations between widely separated scales can persist. In this work I recast UV/IR mixing as a Hilbert-space phenomenon, realised as correlations across renormalisation scales. This formulation is implemented using the Born-Reciprocal Tensor Network (BRTN), a new configuration of tensor network that is globally symmetric under phase-space reciprocity. On this network I prepare the vacuum and reproduce the expected radiative corrections. The resulting renormalisation geometry exhibits memory, with a bridge linking reciprocal representations of IR physics, whose cross-bridge entanglement provides a precise criterion for the viability of an effective description. I analyse when this criterion is met, and show that there is a large-volume limit, with the fundamental scale held fixed, in which the obstruction to a local description scales away: Wilsonian behaviour is restored and renormalisation forgets. The BRTN therefore provides a concrete and calculable platform for UV/IR mixing.

04.
arXiv (CS.CV) 2026-06-11

What Semantics Survive the Connector? Diagnosing VLM-to-DiT Alignment in Video Editing

Flow matching based video generative models have been increasingly relying on prepended Vision-Language Models (VLMs) to handle complex, instruction-based video editing. The prevailing assumption underlying this paradigm is that a connector module can seamlessly align the VLM's rich multi-modal reasoning with the original text embedding space of DiTs. However, we hypothesize that this alignment acts as a severe semantic bottleneck, degrading fine-grained structural variables. Verifying this is challenging, as end-to-end evaluations conflate alignment failures with generation errors, and natural datasets lack disentangled annotations. To rigorously investigate this, we propose a controlled data processing pipeline based on video composition that results in TRACE-Edit, a diagnostic dataset focusing on relation-based editing. Leveraging this dataset, we propose a comprehensive diagnostic protocol to analyze two important designs of meta-query and connector in the existing video editing models. Systematic evaluation of four representative model cases reveals that fine-grained structural semantics can be severely degraded during alignment. Our findings overturn the assumption of lossless semantic transfer, identifying the VLM-to-DiT alignment as a major bottleneck and providing a new diagnostic foundation for future multi-modal alignment architectures.

05.
arXiv (CS.AI) 2026-06-16

Poster: EdgeCitadel – Hybrid NATS-MQTT Orchestration for Edge Multi-Agent Systems

arXiv:2606.14710v1 Announce Type: cross Abstract: Edge-resident AI agents increasingly span home servers, IoT hubs, laptops, and phones, yet their coordination stacks still assume cloud-style transports or a central relay. We present EdgeCitadel, an edge multi-agent orchestration platform built around a single NATS 2.10 server with the built-in MQTT adapter. The design combines MQTT connectivity for heterogeneous agents, JetStream-backed persistence and replay for backend services, direct peer delegation over a shared subject namespace, and a passive aggregator that visualizes and stores traffic without sitting on the delivery path. Our poster highlights the migration from MQTT relay prototypes (common in IoT communication) to the current hybrid architecture and demonstrates a working cross-device testbed spanning ARM64, x64, and Android clients.

06.
arXiv (CS.CL) 2026-06-11

Self-Prompting Small Language Models for Privacy-Sensitive Clinical Information Extraction

Clinical named entity recognition from dental progress notes is challenging because documentation is highly unstructured, domain-specific, and often privacy-sensitive. We developed a locally deployable framework that enables small language models to self-generate, verify, refine, and evaluate entity-specific prompts for extracting multiple clinical entities from dental notes. Using 1,200 annotated notes, we evaluated candidate open-weight models with multi-prompt ensemble inference and further adapted selected models using QLoRA-based supervised fine-tuning and direct preference optimization. Model performance varied substantially, highlighting the need for task-specific evaluation rather than reliance on generic benchmarks. Qwen2.5-14B-Instruct achieved the strongest baseline performance. After DPO, Qwen2.5-14B-Instruct and Llama-3.1-8B-Instruct achieved micro/macro F1 scores of 0.864/0.837 and 0.806/0.797, respectively. These findings suggest that automated prompt optimization combined with lightweight preference-based post-training can support scalable clinical information extraction using locally deployed small language models.

07.
arXiv (CS.CL) 2026-06-12

From Benchmarks to Skills: Low-Rank Factors for LLM Evaluation

Current evaluations of large language models (LLMs) rely heavily on a growing collection of benchmarks and on aggregate benchmark scores, yet it remains unclear what this comparison actually captures, and what these scores reveal about models' underlying capabilities. Here, we propose a new paradigm for LLM evaluation, by asking whether benchmark performance reflects many independent abilities, or rather relies on a small number of shared dimensions. To answer this, we apply Factor Analysis (FA) to a massive performance matrix of LLMs versus benchmarks \((60\times44)\) revealing an intrinsically low-rank structure of that matrix. That is, a small number of latent factors captures most of the structure in the full task space. This low-rank geometry reveals substantial redundancy across existing tasks and explains why many benchmarks appear to be measuring overlapping abilities. We further show that these latent factors correspond to coherent, skill-like, dimensions of LLM behavior. Leveraging this latent skill-space, we deliver three practical tools for LLM evaluation and downstream users: (i)~identifying redundant tasks, (ii)~profiling new models using a small subset of tasks, and (iii)~selecting models aligned with desired skill profiles. Our method provides a solid alternative to the de-facto standard of a single aggregate score, and establishes an interpretable and practical framework for understanding and benchmarking LLM core capabilities.

08.
arXiv (CS.AI) 2026-06-11

From Awareness to Action: Understanding and Overcoming the Research-Practice Gap in Algorithmic Fairness for Public Health

arXiv:2606.11214v1 Announce Type: cross Abstract: Algorithmic fairness is essential for responsible ML-driven public health research, yet its practical implementation remains limited. To investigate this awareness-action gap, we conducted a sequential mixed-methods study comprising expert interviews, an online survey, and systematic mapping. The expert interviews informed the design of the survey, which in turn revealed fragmented definitions of fairness, limited training and guidance, reliance on external sources, and rare use of formal assessment, mitigation, or monitoring. These findings were subsequently mapped onto three established research-practice gap lenses: the Knowledge-Practice Gap, the Knowledge-to-Action Cycle, and the Knowing-Doing Gap, each offering complementary perspectives. Building on this synthesis, we introduce the Fairness-to-Action framework, which integrates methodological, organizational, and systemic dimensions to identify where translation of algorithmic fairness knowledge stalls. Our analysis shows that fairness remains weakly institutionalized, translation mechanisms are externally driven, and system-level priorities continue to emphasize accuracy over fairness. These insights suggest critical leverage points for advancing safe, fair, and ethical ML-driven public health research practice.

09.
arXiv (CS.LG) 2026-06-18

Anomaly Detection for Sparse and Irregular Multivariate Time Series with Latent SDEs

arXiv:2606.18898v1 Announce Type: new Abstract: Multivariate time series anomaly detection (MTSAD) is critical for a wide range of application areas, such as industrial monitoring, cybersecurity, or healthcare. Real-world data is often sparse, irregularly sampled or partially observed, yet existing methods assume uniformly sampled time series. We propose a generative approach based on Latent SDEs that projects the observed time series on a continuous-time stochastic dynamical system, directly being able to handle missing observations and irregular sampling, while also naturally capturing possible cyclic behavior that many real-world use cases inherently possess. Experiments on six anomaly benchmark datasets show that our proposed method ranks first among state-of-the-art baselines. We further demonstrate that our method remains robust under severe data sparsity, while performance significantly degrades for the tested baseline methods. These results highlight latent SDEs as a natural inductive bias for anomaly detection in multivariate time series, especially in presence of real-world irregularities.

10.
arXiv (CS.CV) 2026-06-18

Transformer Geometry Observatory TGO-I: Spectral Geometry Observatory

Despite the widespread adoption of Vision Transformers (ViTs) and their success across numerous computer vision applications, the fundamental understanding of their dimensional and representational geometry remains relatively underexplored. To address this gap, we introduce Transformer Geometry Observatory (TGO), a systematic framework of experiments and analysis pipelines designed to investigate the representational geometry and dynamics of Vision Transformers. TGO-I, the first installment of the framework, focuses on the spectral geometry of ViT representations. Using a ViT-Small/16 model trained on ImageNet-100, we analyze Effective Rank, Stable Rank, Participation Ratio, Spectral Entropy, Spectral Flatness, Spectral Anisotropy, covariance structure, eigenspectra, and singular value spectra throughout training. Our results reveal a consistent increase in dimensional utilization, accompanied by decreasing anisotropy, increasing spectral entropy, increasing participation ratio, and progressively flatter eigenspectra. Contrary to the common intuition that training should concentrate information into a small number of dominant directions, we observe a progressive redistribution of variance across representational dimensions. This phenomenon is particularly pronounced in the final CLS token representation, which exhibits the highest effective dimensionality and lowest anisotropy within the network.

11.
arXiv (CS.AI) 2026-06-18

As You Wish: Mission Planning with Formal Verification using LLMs in Precision Agriculture

arXiv:2606.18519v1 Announce Type: cross Abstract: Though robotic systems are now being commercialized and deployed in various industries, many of these systems are highly specialized and often require an advanced skill set to operate and ensure they perform as instructed. To mitigate this problem, we recently introduced a mission planner leveraging LLMs to synthesize mission plans in precision agriculture based on mission descriptions provided in natural language. While the system demonstrates impressive performance, it also suffers from the inherent ambiguities of natural language. In this paper, we extend our system to address this issue by introducing multiple feedback loops in the planning architecture that leverage linear temporal logic (LTL) to ensure the mission planning system meets the specifications formulated by the user while still using natural language. To mitigate potential bias, this is achieved by using two different commercial LLMs in charge of the specification and verification subtasks. Through extensive experiments, we highlight the strengths and limitations of integrating mission verification into a fully autonomous pipeline, particularly regarding an LLM's ability to generate valuable LTL formulas, and show how our proposed implementation addresses and solves these challenges.

12.
arXiv (CS.CV) 2026-06-19

CalTennis: Large Multi-View Tennis Video Dataset and Benchmark of Monocular-to-3D Pose Estimation

The Caltech Tennis Dataset (CalTennis) is a large-scale video benchmark for evaluating monocular-to-3D pose estimation in the wild. CalTennis comprises over 11 million frames (51 hours) of tennis practice and match play from 40 players, captured with 2-6 synchronized cameras at 60 Hz. It is 10 times larger than existing in-the-wild human motion video datasets and 3 times larger than existing MOCAP-ground-truthed datasets, and it is the first large-scale benchmark to provide synchronized multi-view recordings of expert athletic motion. The multi-view setup enables inexpensive, label-free evaluation of monocular-to-3D pose estimation algorithms. We describe a simple, standardized protocol that enables data collection without specialized equipment or expertise, along with fully automated video calibration and synchronization. Benchmarking state-of-the-art monocular-to-3D pose methods on CalTennis, we find that while 3D joint angle recovery is now quite accurate, all models struggle to estimate depth and foot contact consistently. We further propose two novel performance metrics, footwork and stability, as well as qualitatively study body shape inconsistency. These metrics expose previously underexplored failure modes and point to concrete opportunities for improvement in pose estimation and action analysis.

13.
arXiv (CS.LG) 2026-06-11

Neuro-Relational Programs: Unifying Queries and Neural Computation over Structured Data

arXiv:2606.11946v1 Announce Type: cross Abstract: The conventional approach to deep learning over relational databases applies neural models, such as Graph Neural Networks (GNNs), to a graph representation of the database. Recent approaches instead operate on databases directly, associating tuples with embeddings and extending query mechanisms to jointly process embeddings and relational content. Inspired by these developments, we introduce Neuro-Relational Programs (NRPs), a declarative query language for relational databases whose facts carry numeric vector embeddings. NRPs extend Datalog-style rules with operations that combine, aggregate, and transform embeddings, thereby interleaving relational reasoning and learnable neural components within a single formalism. This yields a general approach to neural computation over relational data: an NRP can be read both as a query plan with trainable components and as a neural architecture with relational structure built in. Natural syntactic fragments of NRPs recover existing architectures and query formalisms. Zero-ary NRPs correspond to non-adaptive query algorithms; monadic NRPs generalize GNN-style message passing and precisely capture Deep Homomorphism Networks, a connection that we extend to frontier-guarded NRPs over databases with row-ids. We characterize the expressive power of unrestricted NRPs with ReLU-FFN transformations by FOCQ, an extension of first-order logic with counting interpreted over real-weighted structures, yielding a precise connection with uniform TC$^0$ over ordered databases. Together, these results establish NRPs as a broad declarative framework for querying and neural computation over relational data.

14.
arXiv (quant-ph) 2026-06-16

Nonlinear cascaded quantum network with giant emitters

arXiv:2404.09829v2 Announce Type: replace Abstract: Chiral quantum optics is central to developing scalable quantum networks, yet existing approaches rely predominantly on linear single-photon regimes. It remains unclear how to generate directional multiphotons. Here we show that giant emitters coupled to nonlinear quantum optical baths enable tunable directional correlated photons, revealing a mechanism for multiphoton directional emission. We demonstrate that the propagation phases of correlated photons, together with the coupling phases of giant emitters, can generate destructive interference in one direction while enhancing emission in the opposite direction, making directionality fully tunable. Building on this mechanism, we introduce a nonlinear cascaded quantum network paradigm mediated by correlated flying qubits, providing a configurable building block enabling distinct many-body applications beyond linear unidirectional setups. These results reveal a rich landscape for engineering multiphoton propagation and correlations through interference in giant emitter-nonlinear bath architectures, offering pathways for quantum networks and strongly correlated light-matter platforms.

15.
arXiv (CS.LG) 2026-06-16

Scalable and Interpretable Representation Alignment with Ordinal Similarity

arXiv:2606.16379v1 Announce Type: new Abstract: Evaluating representation similarity is fundamental to representation learning. However, existing metrics suffer from significant limitations: they lack interpretability due to shifting baselines, lack robustness to outliers, and are computationally intractable for large datasets, forcing reliance on heuristic approximations. To address this, we develop an ordinal-similarity framework, instantiated by the Triplet (TSI) and Quadruplet (QSI) Similarity Indices, which measure alignment by quantifying the consistency of ordinal relationships. We theoretically demonstrate this formulation is inherently interpretable, robust to outliers, and computationally efficient. Finally, we establish a formal equivalence between TSI and local neighborhood alignment, measured by Mutual Nearest Neighbors. Empirically, we validate these properties and show that ordinal similarity offers a scalable approach to measuring alignment, enabling practitioners to better understand and design representations.

16.
arXiv (CS.AI) 2026-06-12

PRISMR: Overcoming Parse Collapse in Multimodal Listwise Ranking via Parameterized Representation Internalization

arXiv:2606.12942v1 Announce Type: new Abstract: Generative listwise ranking with Large Multimodal Models (LMMs) aims to capture global list context in a single forward pass, but its effectiveness degrades in long-context multimodal scenarios. We identify a recurring failure mode, parse collapse, where the autoregressive decoder produces fluent yet incomplete rankings by silently omitting candidates and terminating early. This failure stems from limited context utilization rather than simple formatting mistakes, making prompt engineering and constrained decoding insufficient. We propose PRISMR (Parameterized Representation Internalization for Semantic Multimodal Ranking), a framework that replaces transient in-context list processing with parametric structural conditioning. PRISMR uses a lightweight hypernetwork to encode multimodal candidates in parallel and generate item-specific LoRA weights, which are synthesized into an instance-specific adapter for a LMM. This paradigm enables more robust internalization of list structure while preserving the base model. We further introduce a large-scale multimodal review-ranking benchmark for evaluation. Experiments demonstrate that PRISMR substantially reduces parse collapse, improves listwise ranking performance, and transfers effectively across domains and instruction-tuned backbones.

17.
arXiv (CS.LG) 2026-06-18

DIPHINE: Diffusion-based $\Phi$-ID Neural Estimator

arXiv:2606.18997v1 Announce Type: new Abstract: Uncovering the true informational architecture of real-world complex systems requires disentangling how their components uniquely store, redundantly share, and synergistically integrate information over time. Integrated Information Decomposition ($\Phi$ID) is a framework for decomposing the information dynamics of multivariate systems into sixteen non-overlapping atoms that characterize redundant, unique, and synergistic modes of information storage, transfer, and integration. Existing methods to compute $\Phi$ID are restricted to Gaussian or discrete systems, preventing its application to continuous non-Gaussian dynamical systems. We address this limitation by proposing DIPHINE (Diffusion-based $\Phi$-ID Neural Estimator), the first neural estimator that leverages score-based diffusion models to jointly estimate all the mutual information terms required by $\Phi$ID from a single amortized network, recovering the sixteen atoms through Möbius inversion. We provide a theoretical analysis of error propagation through the inversion, showing that the Jacobian of the mapping from mutual informations to atoms is integer-valued and that the synergy-to-synergy atom is provably the hardest to estimate. We demonstrate accurate recovery of ground-truth atoms on synthetic benchmarks, superior performance compared to established mutual information estimators, and the ability to extract physiologically interpretable information-dynamic structure on an application involving real data without any distributional assumptions.

18.
arXiv (CS.CV) 2026-06-18

Quantile Transfer for Reliable Operating Point Selection in Visual Place Recognition

Visual Place Recognition (VPR) is a key component for localisation in Global Navigation Satellite System (GNSS)-denied environments, but its performance critically depends on selecting an image matching threshold (operating point) that balances precision and recall. Thresholds are typically hand-tuned offline for a specific environment and fixed during deployment, leading to degraded performance under environmental change. We propose a method that automatically selects the operating point of a VPR system to maximise recall at 100% precision. The method uses a small calibration traversal with known correspondences and transfers thresholds to deployment via quantile normalisation of similarity score distributions. This quantile transfer ensures that thresholds remain stable across calibration sizes and query subsets. Experiments with seven state-of-the-art VPR techniques across five benchmark datasets demonstrate that our proposed approach consistently outperforms existing baselines, enabling the underlying VPR technique to operate at 100% precision in approximately twice as many deployment scenarios (median improvement), while retrieving up to 29% more correct matches at that precision. The method eliminates manual tuning by adapting to new environments and generalising across operating conditions. Our code is available at https://github.com/DhyeyR-007/Quantile-Transfer-for-Reliable-VPR.

19.
arXiv (quant-ph) 2026-06-19

Quantum models with the Yang-Lee phase transition

arXiv:2606.19732v1 Announce Type: cross Abstract: In this article, we present four different $1+1$D quantum models that realize the Yang-Lee (YL) phase transition under a deformation that preserves $PT$ symmetry. These are the antiferromagnetic Ising spin chain in transverse and longitudinal magnetic fields, the massive Schwinger model, the Blume-Capel model, and the three-state quantum clock model. Using the state-operator correspondence, we identify the YL critical point, compute the scaling dimensions of the lowest operators in each model, and find perfect agreement with the exact results for the YL criticality in two dimensions. Using bosonization for the Schwinger model and the Polyakov-Hubbard transformation for the other models, we show that in all of these quantum models the YL critical point is described, as expected, by a massless bosonic field with an $i \phi^3$ interaction. In the quantum clock model, this critical field interacts with a massive bosonic field, and we identify the massless and massive states in the Hamiltonian spectrum. In addition, we numerically compute the two-point function of $\phi$ at the Yang-Lee critical point and show that it grows with distance, in agreement with theoretical expectations.

20.
arXiv (CS.CL) 2026-06-16

Rhythm of the Deep: A Computational-Linguistic Test of Duality of Patterning in Sperm Whale Codas

Human language has often been described as combining structure at two levels: lower-level units combine into larger units, which then combine into larger sequences. We test for this design feature, duality of patterning, in sperm whale codas using 1,483 codas from the Dominica Sperm Whale Project. Because acoustic similarity can imitate symbolic structure, we treat the problem as computational-linguistic structure discovery from continuous audio rather than as a direct claim about language or meaning. We use a consensus of frozen audio encoders, held-out structural tests, per-statistic nulls, and acoustic-null recoverability gates. The evidence supports a narrow two-tier architecture. At the lower tier, clicks compose into codas not by a stable ordered rule, but by which clicks are present together with their inter-click rhythm. At the upper tier, coda tokens show bout-level sequential dependence, with an NSB second-order transfer-entropy lift of 0.132 bits (p = 0.002). Under tempo scaling, encoder-derived click identity is strongly rate-bound, while coda identity remains substantially more stable, yielding a measurable abstraction gradient across the click-to-coda step. Rhythm-only baselines recover substantial lower-tier structure but fail to reproduce the upper-tier sequential-dependence signal. We do not claim language, semantics, perception, or human-like phonemes. Instead, we report representation-level evidence for a duality-of-patterning-like architecture whose lower tier is rhythmic rather than segmental, and provide a portable null-controlled framework for testing combinatorial structure in induced acoustic token systems.

21.
PLOS Computational Biology 2026-06-11

A zero-parameter first-principles gate framework for full-length TP53 missense variant interpretation

by Masamichi Iizumi Missense variant interpretation often achieves useful predictive performance but remains mechanistically opaque, particularly in proteins that combine structured domains with intrinsically disordered regions (IDRs). We developed Gate & Channel, a zero-parameter, first-principles framework for full-length TP53 missense variant analysis in which each prediction is generated by explicit IF-THEN gates derived from physicochemistry, geometry, structural constraints, and polymer physics rather than fitted weights. Variants are evaluated across independent channels representing distinct physical failure modes; a variant is predicted disruptive if any gate closes. A second hierarchical layer (“Geta”) encodes physically grounded post-closure exceptions, allowing sensitivity and specificity to be improved on disjoint variant populations. The v18 framework consists of 12 channels and 2 Getas spanning structured domains and IDRs, capturing DNA-contact disruption, Zn coordination, burial-dependent packing, secondary-structure compatibility, post-translational modification chemistry, short linear motif disruption (including a multi-partner coupled-folding face), proline-directed kinase recognition, and IDR-specific proline and glycine backbone constraints. Across 1,369 TP53 missense variants, the framework achieved 84.5% sensitivity and 89.1% positive predictive value, with 90.9% sensitivity preserved in the DNA-binding core and all 9/9 hotspot mutations captured. A post hoc audit of discordant IDR calls indicated that many apparent false positives had plausible molecular rationales, consistent with a distinction between molecular mechanism disruption and clinical penetrance. Applied to KRAS, TDP-43, and BRCA1, the same channels capture the dominant pathogenic mechanisms in each protein as a proof of principle, while residual missed variants name specific gates yet to be written. The framework is distributed as the open-source Python package pathogenicity-gates (v0.5.1, MIT). These results show that a substantial fraction of full-length TP53 missense variation can be resolved through explicit, auditable physical gates that carry meaning beyond TP53, with each remaining failure naming the next rule to be written.

22.
medRxiv (Medicine) 2026-06-17

A multistate model of frailty progression after severe infections in adults >=65 years in England: a matched-cohort study

Background Evidence on frailty progression following severe infections is limited. We compared rates of transition to greater frailty or death between adults with and without severe infection in England. Methods We conducted a matched-cohort study among adults aged [≥]65 years (1,452,117: median age 76 years, 45% male) in Clinical Practice Research Datalink Aurum (2006-2019). Adults with severe infection (hospitalised primarily due to infection) were matched on calendar time to individuals without severe infection on age, sex, and primary care practice. The admission date was used as index date and same was assigned to matched unexposed adults. We measured frailty using Electronic Frailty Index, a proportion of 36 health deficits in validated categories (Fit 0-0.12, Mild >0.12-0.24, Moderate >0.24-0.36, Severe >0.36). In a time-varying Markov multistate model, we focused on forward transitions from baseline or intermediate frailty states to higher states or death. For each transition, we used Cox regression to estimate cause-specific transition hazard ratios (HR) with 95% confidence intervals (CIs), comparing adults with and without severe infection. We adjusted for baseline frailty score, age, sex, deprivation, harmful alcohol use, smoking, and primary care infection history 5 years before index date. We estimated state occupancy probabilities, and expected length of stay (ELOS) in each state at year five among adults with and without severe infection. We explored effect modification by infection type. Results Across all transitions, severe infection was associated with higher adjusted hazards of transitioning to worsening frailty or death, HR, 95% CI: (fit to: mild[1.56, 1.54-1.58], moderate[2.51, 1.79-3.51], death[4.57, 4.50-4.65]; mild to: moderate[1.52, 1.50-1.53], severe[1.90, 1.43-2.52], death[2.67, 2.64-2.70]; moderate to: severe[1.40, 1.38-1.42], death[1.87, 1.85-1.90]; severe to death[1.48, 1.46-1.50]). Transition hazard ratios were strongest for lower respiratory tract infections, followed by sepsis, urinary tract infections, meningitis/encephalitis, gastroenteritis, and skin and soft tissue infections. At five years, adults with severe infection had higher probabilities of transitioning to greater frailty or death across all transitions and lower ELOS in each frailty state than those without severe infection. Interpretation Severe infections may accelerate frailty deterioration in older age. Prevention through vaccination, early detection, and prompt management may help mitigate this decline.

23.
Nature Medicine 2026-06-10

Dual-target gene therapy in Parkinson’s disease: a multicenter phase 1 trial

作者:

Restoring striatal dopamine synthesis is a promising gene therapy strategy for Parkinson’s disease. Previous adeno-associated virus-mediated aromatic L-amino acid decarboxylase (AADC) monotherapies remain dependent on exogenous levodopa, whereas multigene delivery is constrained by strict adeno-associated virus packaging limits. A ‘dual approach’ targeting the two rate-limiting enzymes, tyrosine hydroxylase (TH) and AADC, offers the potential for autonomous dopamine synthesis. We report the 12-month primary safety and tolerability outcomes of a multicenter, open-label, dose-escalation, phase 1 trial evaluating BBM-P002, a new adeno-associated virus vector—AAVT42—codelivering constitutively active TH and AADC. Ten participants with moderate-to-advanced Parkinson’s disease were enrolled and received bilateral intraputaminal infusions across doses of 4.0 × 1011 vg (Cohort 1; n = 1), 6.0 × 1011 vg (Cohort 2; n = 2), 1.0 × 1012 vg (Cohort 3; n = 2) and 1.2 × 1012 vg (Cohort 4; n = 5). The trial achieved its primary outcome, as BBM-P002 demonstrated a favorable safety and tolerability profile within 12 months post-treatment. No dose-limiting toxicities or drug-related serious adverse events occurred. A total of 23 adverse events were reported, all judged unrelated to BBM-P002 and primarily mild and transient. Systemic toxicity and clinically meaningful immunogenicity were absent. In conclusion, intraputaminal delivery of BBM-P002 was safe and well tolerated in this phase 1 trial, supporting continued clinical development. ClinicalTrials.gov registration: NCT05822739 . Phase 1 results reveal that BBM-P002, a dual-target gene therapy co-delivering TH and DDC, is safe and well tolerated in Parkinson’s disease, with 12-month motor improvements signaling therapeutic potential.

24.
arXiv (quant-ph) 2026-06-17

Singular Vector Finite Element Basis Functions for Tetrahedra in Complex Electromagnetic Geometries

arXiv:2606.18140v1 Announce Type: cross Abstract: Electromagnetic finite element method (FEM) implementations using traditional basis functions struggle to accurately represent field behavior near singular features such as conducting wedges. To combat this, specialized singular basis functions have been introduced to directly model the singular fields in these regions, leading to substantially improved performance. While these efforts have been pursued extensively in 2D, few functions have been developed for 3D elements. In this work, we develop basis functions for this in tetrahedra. Unlike prior functions, these basis functions are additive, meaning they are included alongside the standard vector basis functions to achieve more robust performance. Further, these functions are designed to be adaptable to tetrahedra touching several unique singular features by using combinations of basis functions singular with respect to each node and edge in the element, making them applicable to highly complex geometries. Higher-order interpolatory versions of the basis functions for modeling singular behavior with greater accuracy are also provided. These basis functions lead to substantial improvements in accuracy relative to the standard basis functions, and allow otherwise expensive simulations to be performed at far lower costs. As an application example, we perform simulations to extract critical quantities for designing superconducting qubits that significantly depend on the behavior of singular fields. In Ansys HFSS, this took 21.27 hours and a peak memory usage of 6.23 TB with 800 processors available, while using our singular basis functions achieved comparable results in 196 seconds while using 27.24 GB of memory and only 16 processors. Due to these benefits, our singular basis functions could be applied to enable design optimization of electromagnetic geometries with dominantly singular behavior, such as superconducting qubits.

25.
arXiv (CS.CL) 2026-06-15

Trusted Uncertainty in Large Language Models: A Unified Framework for Confidence Calibration and Risk-Controlled Refusal

Deployed language models must decide not only what to answer but also when not to answer. We present UniCR, a unified framework that turns heterogeneous uncertainty evidence including sequence likelihoods, self-consistency dispersion, retrieval compatibility, and tool or verifier feedback into a calibrated probability of correctness and then enforces a user-specified error budget via principled refusal. UniCR learns a lightweight calibration head with temperature scaling and proper scoring, supports API-only models through black-box features, and offers distribution-free guarantees using conformal risk control. For long-form generation, we align confidence with semantic fidelity by supervising on atomic factuality scores derived from retrieved evidence, reducing confident hallucinations while preserving coverage. Experiments on short-form QA, code generation with execution tests, and retrieval-augmented long-form QA show consistent improvements in calibration metrics, lower area under the risk-coverage curve, and higher coverage at fixed risk compared to entropy or logit thresholds, post-hoc calibrators, and end-to-end selective baselines. Analyses reveal that evidence contradiction, semantic dispersion, and tool inconsistency are the dominant drivers of abstention, yielding informative user-facing refusal messages. The result is a portable recipe of evidence fusion to calibrated probability to risk-controlled decision that improves trustworthiness without fine-tuning the base model and remains valid under distribution shift.